The cholinergic neuronal system can be found in the central nervous system (CNS), in the autonomic nervous sytem, and in the skeletal motor system. Acetylcholine (ACh) is the neurotransmitter in all ganglia, the neuromuscular junction, and the post-ganglionic synapses of the cholinergic nervous system. Acetylcholine is normally an excitatory neurotransmitter that binds to nicotinic and muscarinic receptors.
In particular, acetylcholinesterase (AChE) is an enzyme that hydrolyzes and thereby deactivates ACh after it binds to a receptor. This enzyme is present in all peripheral and central junctional sites and in certain cells of the body. Acetylcholinesterase (AChE), which is sometimes called true or specific cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. AChE may be distinguished from other cholinesterases by substrate and inhibitor specificities and by regional distribution. Its distribution in brain correlates with cholinergic innervation and subfractionation shows the highest level in nerve terminals.
It is generally accepted that the physiological role of AChE is the rapid hydrolysis and inactivation of acetylcholine. Inhibitors of AChE show marked cholinominetic effects in cholinergically-innervated effector organs and have been used therapeutically in the treatment of glaucoma, myasthenia gravis and paralytic ileus.
In some circumstances, it is desirable to stimulate acetylcholine receptors. One method involves the use of indirect agonists, such as anticholinesterase drugs, which inhibit the hydrolysis of ACh by AChE. When an anticholinesterase drug blocks AChE and inhibits the destruction of released ACh, a higher neurotransmitter level and increased biological response result. For example, the alkaloid physostigmine, trimethyl-1,3a,8-hexahydro-1,2,3,3a,8,8a-pyrrol[2,3-b]indole-5(3aS,8aR)met hylcarbamate, which can be isolated from the seeds of the Calabar bean, has been found to be an anticholinesterase drug.
Alzheimer's disease is a neurodegenerative disease of the brain leading to severely impaired cognition and functionality, in which there is a significant loss of the cerebral cortex acetylcholine concentration. It is believed that degeneration of the cholinergic pathways in the CNS may be a principal cause of dementia of the Alzheimer's type. This disease leads to progressive regression of memory and learned functions. Since the average age of the population is on the increase, the frequency of Alzheimer's disease is increasing and requires urgent attention.
Cholinesterases are found throughout the body, both in the brain and in blood serum. However, only brain acetylcholinesterase (AChE) distribution is correlated with central cholinergic innervation. This same innervation is suggested to be weakened in Alzheimer patients.
It has been suggested that cholinergic agonists, such as the anticholinesterase drugs, are useful in the treatment of Alzheimer's disease. In particular, physostigmine (eserine), being an inhibitor of acetylcholinesterase, has been used in its treatment. The administration of physostigmine has the drawback of being considerably limited by its short half-life of effect, poor oral bioavailability, and severe dose-limiting side-effects, particularly towards the digestive system. Thus, there is a need in the art for new forms of drugs for the treatment of this disease.
The enantiomers of physostigmine and pharmaceutically active physostigmine-like compounds, such as the compounds described in U.S. Pat. Nos. 4,791,107, 4,831,155, 4,900,748, 4,914,102 or 4,971,992, are under investigation for the treatment of Alzheimer's disease.
The pharmacokinetics and pharmacodynamics of physostigmine upon oral and intravenous administration to a mammal have been examined (see for example Somani, et al., Biopharm. Drug Dispo., 10, 187-203 (1989); Giacobini, et al., Neuropharm., 26, 831-836 (1987); Somani, et al., Drug Metab. Dispo., 15, 627-633 (1987); Somani, et al., Fund. Appl. Toxicol., 6, 327-334 (1986); Unni, et al., Drug Metab. Dispo., 14, 183-189 (1986); Boyer, et al., Arch. int. Pharmacodyn., 278 180-192 (1985); Somani, et al., Eur. J. Drug Metab. Pharmacokin., 10, 343-349 (1985); Hemsworth, et al., J. Pharm. Sci., 59, 118-120 (1970)). The metabolism of physostigmine upon incubation with mouse liver microsomes has also been examined (Isaksson, et al., J. Chromatog., 419, 165-175 (1987)). In particular, it has been reported that physostigmine is metabolized to eseroline and at least three other unknown metabolites (Somani, et al., Biopharm. Drug Dispo., 10, 187-203 (1989)). Mammalian metabolites of heptylphysostigmine, trimethyl-1,3a-8-hexahydro-1,2,3,3a,8,8a-pyrrol[2,3-b]indole-5(3aS,8aR)hep tylcarbamate, however, have not been previously reported.
Accordingly, with the present invention there are provided derivatives of physostigmine which have cholinesterase inhibitory activity.